B cells are indispensable for normal immune surveillance systems and their dysfunction leads to the development of autoimmune diseases and B cell malignancies. While progress has been made in elucidating the molecular events underlying normal B cell development, further research is required to address the limitations of current therapeutic strategies. The objective of this application is to further clarify the role of the proto-oncogene Leukemia/lymphoma Related Factor (LRF, also known as Pokemon) in normal and malignant B cell development. This will be done by employing a series of mutant mouse models and molecular approaches. This proposal was formulated based on our findings that: 1) LRF acts as a proto-oncogene and is highly expressed in Non-Hodgkin Lymphoma tissues: 2) LRF opposes Notch function at the hematopoietic stem cell (HSC) level and is indispensable for normal B cell development in the bone marrow and 3) formation of Germinal Centers (GCs), where critical molecular events for both normal (antibody diversification) and malignant (oncogenic transformation) B cell function take place, is severely impaired in B cell specific LRF conditional knockout (KO) mice. The central hypothesis of the application is that LRF is required for the maintenance of normal and malignant mature B cells and thus represents a potential therapeutic target for subsets of B cell lymphomas as well as autoimmune diseases. The rationale for the proposed research is that it is expected to provide a greater understanding of normal and malignant B cell development, facilitating the advancement of novel therapeutic strategies. Guided by strong preliminary data, we will test our hypothesis by pursuing two specific aims: 1) Determine the role of LRF in normal and malignant mature B cell development in vivo; 2) Identify the molecular mechanisms by which LRF functions in GCB cells. Under the first aim, we will determine the role of LRF in B cells by employing both loss of function (LRF conditional KO) and gain of function (LRF tissue specific knockin) mice models. Under aim #2, we will identify key transcription modifiers that interact with LRF via a proteomic approach. The proposed project is innovative because it takes advantage of unique in vivo mouse models (aim #1), capitalizing on underlying molecular mechanisms, and employs novel genome-wide molecular approaches (aim #2). These studies will have an important positive impact by increasing our understanding of normal and malignant B cell development, as well as by facilitating the development of new therapeutic strategies for B cell malignancies and autoimmune diseases. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health as elucidation of the molecular mechanism underlining normal B cell development will expedite the development of innovative therapeutic strategies targeting B cell- associated malignancies as well as auto-immune diseases.